1. Field of the Invention
The present invention relates generally to the fields of molecular biology, oncology and gene therapy. More particularly, it concerns the identification of a novel tumor suppressor gene, WWOX, which is mutated in several cancers. The invention provides methods of utilizing the tumor suppressor gene as a cancer diagnostic tool. The invention also provides methods to identify patients with a higher susceptibility to certain cancer types involving the status of the WWOX tumor suppressor. Furthermore, the invention provides methods for the treatment of cancers comprising administering a therapeutic nucleic acid and/or polypeptides based on the tumor suppressor gene.
2. Description of Related Art
Second only to heart disease, cancer is the leading cause of death in the United States, striking one in two men and one in three women (Landis, 1998). Normal tissue homeostasis is a highly regulated process of cell proliferation and cell death. The development of cancer is the culmination of complex, multistep biological processes, occurring through the accumulation of genetic alteration which typically cause an imbalance in the genes controlling either cell proliferation or cell death. Many if not all of these alterations involve specific cellular growth-controlling genes that are mutated. These genes typically fall into two categories: proto-oncogenes and tumor suppressor genes. Mutations in genes of either class generally lead to abnormal cell-growth and result in cancers.
The function of tumor suppressor genes is to antagonize cellular proliferation. When a tumor suppressor gene is inactivated, for example by mutations such as deletions or point mutations, the cell's regulatory machinery for controlling growth is upset. Several studies have shown that the neoplastic tendencies of such mutated cells can be suppressed by the addition of a nonmutated (wild-type) version of the tumor suppressor gene that expresses its gene product (Levine, 1995). For example, a point mutation in the p53 tumor suppressor protein results in the complete loss of wild-type p53 function (Vogelstein and Kinzler, 1992) and acquisition of “dominant” tumor promoting function.
Currently, there are few effective options for the diagnosis and treatment of many common cancer types. The most conventional options of cancer treatment are surgery, radiation therapy and chemotherapy. Typically, surgical methods are used for the diagnosis (by surgical biopsy) and treatment of cancer (surgery to remove cancerous growths). However, if the cancer has metastasized and is widespread, surgery is unlikely to result in a cure and an alternate approach must be taken. Radiation therapy, chemotherapy and immunotherapy are other forms of cancer treatment (Mayer, 1998; Ohara, 1989; Ho et al., 1998). However, both radiation therapy and chemotherapy are associated with numerous side effects since normal cells are also affected and these include skin irritation, difficulty swallowing, dry mouth, nausea, diarrhea, hair loss, mouth sores, fatigue, bleeding to name a few. Immunotherapy, a rapidly evolving area in cancer research, is yet another option for the treatment of certain types of cancers which unfortunately has not been sufficient to prevent most tumor growths.
Gene therapy is another emerging field in biomedical research with a focus on the treatment of disease by the introduction of therapeutic recombinant nucleic acids into somatic cells of patients. Various clinical trials using gene therapies have been initiated and include the treatment of various cancers, AIDS, cystic fibrosis, adenosine deaminase deficiency, cardiovascular disease, Gaucher's disease, rheumatoid arthritis, and others.
While there are some gene therapies for cancer treatments in clinical trials, not all cancer causing genes have been identified. As mutations in oncogenes and tumor-suppressor genes are the major causes for loss of cell-cycle control, there is a growing need to identify more genes of these two classes. Some examples of the tumor suppressor genes targeted for anticancer genetherapies are p53 and retinoblastoma. However, not all cancers are due to mutations of these two genes. Given the diverse types of cancers and the large population affected by cancer there is need to identify more such tumor suppressor genes involved in cancer to find better and effective anticancer treatments.